Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing an individual to an increased risk of fracture. Osteoporosis affects 20 million people in the United States and leads to an estimated 1.2 million bone fractures annually. It has been estimated that approximately 30 percent of all post-menopausal Caucasian women will suffer from an osteoporotic fracture. Osteoporosis may be treated and/or prevented using a number of different active agents such as antiresorptive agents (e.g., estrogen, selective estrogen receptor modulators, bisphosphonates, and calcitonin) or anabolic agents (e.g., parathyroid hormone). Antiresorptive agents impart skeletal benefits by reducing osteoclastic resorption of bone, thus causing a reduction in bone remodeling and an increase in bone mineral density (BMD). Anabolic agents generally reduce risk of osteoporotic fracture by stimulating new bone formation.
Human parathyroid hormone is a naturally occurring protein that is secreted as a linear 84 amino acid peptide. Parathyroid hormone regulates calcium concentration in the blood stream by stimulating osetoclasts to reabsorb calcium from bone, enhancing calcium absorption from the small intestine and suppressing calcium loss in the urine. Hock et al., J. Bone Miner. Res 4:449-458 (2002). Synthetic parathyroid hormones have been developed as medicaments to enhance the uptake of calcium and to stimulate new bone formation. One recombinant parathyroid hormone is Forteo® (teriparatide (rDNA origin), recombinant human parathyroid hormone (1-34)) (available from Eli Lilly and Company of Indianapolis, Ind.). Forteo® is administered by subcutaneous injection for (1) the treatment of postmenopausal women with osteoporosis who are at high risk for fracture, and (2) to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.
The medical condition, hypoparathyroidism may have a number of divergent causes. For example, removal of the parathyroid glands in thyroid surgery (thyroidectomy) is a recognized cause. It is now uncommon, as surgeons generally spare them during the procedure after identifying them. Autoimmune invasion and destruction is the most common non-surgical cause. It can occur as part of autoimmune polyendocrine syndromes. Hemochromatosis can lead to iron accumulation and consequent dysfunction of a number of endocrine organs, including the parathyroids. Absence or dysfunction of the parathyroid glands is one of the components of chromosome 22q11 microdeletion syndrome (other names: DiGeorge syndrome,
Schprintzen syndrome, velocardiofacial syndrome). Magnesium deficiency, some very rare diseases and idiopathic (of unknown cause), occasionally familial causes lead to hypoparathyroidism.
The physiologic function of PTH is the maintenance of sufficient calcium levels. This is achieved by bone resorption, renal reabsorption of calcium (in the distal tubule) and Vitamin D3 (1,25—OH-D3) synthesis (also in the kidney) from Vitamin D1 (25—OH-D3).
Severe hypocalcemia, a potentially life-threatening condition, is treated as soon as possible with intravenous calcium. Long-term treatment of hypoparathyroidism is with calcium and vitamin D3 supplementation (D1 is ineffective in the absence of renal conversion). A synthetic or naturally derived form of PTH, such as in the present invention, might become the treatment of choice for PTH supplementation in patients with hyperparathyroidism.
Buccal delivery is a more preferable method of administering drugs and offers several advantages over subcutaneous injection. Typically, a buccal dosage form is placed in the buccal cavity between the gum and the cheek, where it dissolves in the patient's saliva, releasing the drug into the buccal cavity in close proximity to the capillary bed of the oral mucosa. The drug then enters the blood in the capillary bed by diffusion through the mucosal tissue and is distributed in the bloodstream to the rest of the body.
Buccal administration is less invasive and results in greater patient compliance compared to subcutaneous injection. Furthermore, unlike oral administration, buccal administration avoids the possibility that the drug will be destroyed in the gastrointestinal tract before it can be absorbed, and eliminates first-pass inactivation in the liver after absorption.
Therefore, there is a need for a parathyroid hormone formulation which can be buccally administered.